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1.
Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis.
Ho Lee, Y, Gyu Song, G
Journal of clinical pharmacy and therapeutics. 2020;(4):674-681
Abstract
WHAT IS KNOWN AND OBJECTIVE Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed. METHODS We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA. RESULTS AND DISCUSSION Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo. WHAT IS NEW AND CONCLUSION All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.
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2.
Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial.
Molina, JM, Squires, K, Sax, PE, Cahn, P, Lombaard, J, DeJesus, E, Lai, MT, Xu, X, Rodgers, A, Lupinacci, L, et al
The lancet. HIV. 2018;(5):e211-e220
Abstract
BACKGROUND Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. METHODS In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than -10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. FINDINGS Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI -1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one (<1%) participant of each group. INTERPRETATION In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. FUNDING Merck & Co.
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One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.
Inati, A, Kahale, M, Sbeiti, N, Cappellini, MD, Taher, AT, Koussa, S, Nasr, TA, Musallam, KM, Abbas, HA, Porter, JB
Pediatric blood & cancer. 2017;(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
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4.
Multidisciplinary evaluation at baseline and during treatment improves the rate of compliance and efficacy of deferasirox in elderly myelodysplastic patients.
Del Corso, L, Biale, L, Parodi, EL, Russo, R, Filiberti, R, Arboscello, E
International journal of clinical oncology. 2017;(2):380-386
Abstract
BACKGROUND Deferasirox (DFX) is used to reduce iron levels in patients with myelodysplastic syndrome (MDS) who develop iron overload after chronic red blood cell infusions. However, DFX can be associated with renal and gastrointestinal toxicities, which may cause treatment interruption or discontinuation. This study aimed to determine the effectiveness and safety of DFX in patients with MDS. METHODS This multicenter, retrospective, observational study was conducted at two hospitals in Italy. Elderly patients with transfusion-dependent MDS received DFX for up to 12 months and were divided into two groups: group A comprised patients who were not under multidisciplinary assessment; group B comprised patients under multidisciplinary control. Treatment effectiveness was estimated by monitoring the serum ferritin (SF) levels throughout the study. Any treatment-related adverse events (AEs), clinically relevant analytical alterations, and reasons for treatment discontinuation were monitored. RESULTS The study included 44 patients (13 female, 31 male; median age 77.0 years). At 3 months, SF levels decreased by ≥20 % in 29 and 31 % of patients in groups A and B, respectively, in 17 and 36 % of patients at 6 months, and in 22 and 58 % at 12 months. The most common AEs were diarrhea and increased serum creatinine, which were more frequent in group A. The discontinuation rate after renal AE was 15 and 5 % in groups A and B, respectively. CONCLUSION Multidisciplinary evaluation can be an effective strategy for monitoring renal function in patients on DFX therapy, to improve treatment adherence and overall efficacy in elderly patients with MDS.
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Review of empagliflozin monotherapy for previously untreated patients with type 2 diabetes mellitus: Comparison with sitagliptin.
Cornell, S
Postgraduate medicine. 2015;(3):277-81
Abstract
This Practice Pearl provides a review and brief commentary of the 24-week, double-blind, parallel-group, randomized, Phase III study by Roden et al., which assessed the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin, 10 mg or 25 mg as monotherapy, versus placebo and the dipeptidyl peptidase-4 inhibitor sitagliptin, in previously untreated patients with type 2 diabetes mellitus (T2DM). Compared to placebo, empagliflozin improved glycemic control, with additional benefits on bodyweight and systolic blood pressure, versus placebo and sitagliptin. Treatment was well tolerated. The authors concluded that empagliflozin is a potential new approach to treat patients with T2DM who are inadequately controlled with diet and exercise alone. This paper advances our understanding of empagliflozin, which so far, appears to be a promising therapeutic option for the management of patients with T2DM.
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6.
Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes.
Tremblay, AJ, Lamarche, B, Deacon, CF, Weisnagel, SJ, Couture, P
Metabolism: clinical and experimental. 2014;(9):1141-8
Abstract
UNLABELLED Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. OBJECTIVE The objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. METHODS AND RESULTS Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m²) were recruited into this double-blind, cross-over study using sitagliptin (100mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P=0.006), interleukin (IL)-6 (24.7%, P=0.04), IL-18 (7.3%, P=0.004), secreted phospholipase-A₂ (sPLA₂) (12.9%, P=0.04), soluble intercellular adhesion molecule-1 (5.3%, P=0.002), and E-selectin (5.9%, P=0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r=0.41, P=0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. CONCLUSIONS Treatment with sitagliptin for 6 weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities.
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7.
Diabetes-related quality measure attainment: canagliflozin versus sitagliptin based on a pooled analysis of 2 clinical trials.
Bailey, RA, Vijapurkar, U, Meininger, GE, Rupnow, MF, Blonde, L
The American journal of managed care. 2014;(13 Suppl):s296-305
Abstract
OBJECTIVE To evaluate attainment of diabetes-related quality measures with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus. STUDY DESIGN This post hoc analysis used pooled data from two 52-week, randomized, double-blind, phase 3 clinical trials that evaluated the comparative efficacy of canagliflozin and sitagliptin. One trial evaluated patients on metformin at baseline with add-on canagliflozin 100 mg, canagliflozin 300 mg, or sitagliptin 100 mg; the other trial evaluated patients on metformin and a sulfonylurea at baseline with add-on canagliflozin 300 mg or sitagliptin 100 mg. METHODS Individual diabetes-related quality measures, including glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), and change in body weight, were assessed. RESULTS At baseline, the proportions of patients meeting criteria for all quality measures were similar between groups. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 100 mg demonstrated either comparable or superior glycemic control. Additionally, canagliflozin 100 mg versus sitagliptin 100 mg demonstrated superior attainment of BP, BMI, and weight-related quality measures; no difference was seen with respect to LDL-C. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 300 mg demonstrated superior glycemic control at all thresholds of A1C, and superior BP, BMI, and weight-related quality measures; there was no difference in LDL-C quality measure attainment. CONCLUSION We evaluated the comparative efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg on quality measure attainment after 52 weeks of treatment. Compared with sitagliptin 100 mg, canagliflozin 100 mg demonstrated comparable or superior attainment of diabetes-related quality measures. Compared with sitagliptin 100 mg, canagliflozin 300 mg demonstrated superior diabetes-related quality measure attainment, including glycemic, BP, and weight-related quality measures; there was no difference in LDL-C quality measure attainment between either dosage of canagliflozin and the 100-mg dosage of sitagliptin.
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8.
Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients.
Ayaori, M, Iwakami, N, Uto-Kondo, H, Sato, H, Sasaki, M, Komatsu, T, Iizuka, M, Takiguchi, S, Yakushiji, E, Nakaya, K, et al
Journal of the American Heart Association. 2013;(1):e003277
Abstract
BACKGROUND Endothelial dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes (T2DM). Glucagon like peptide-1 (GLP-1) reportedly exerts vasodilatory actions, and inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme-degrading GLP-1, are widely used to treat T2DM. We therefore hypothesized that DPP-4 inhibitors (DPP-4Is) improve endothelial function in T2DM patients and performed 2 prospective, randomized crossover trials to compare the DPP-4I sitagliptin and an α-glucosidase inhibitor, voglibose (in study 1) and the DPP-4Is sitagliptin and alogliptin (in study 2). METHODS AND RESULTS In study 1, 24 men with T2DM (46±5 years) were randomized to sitagliptin or voglibose for 6 weeks without washout periods. Surprisingly, sitagliptin significantly reduced flow-mediated vasodilatation (FMD; -51% compared with baseline, P<0.05) of the brachial artery despite improved diabetic status. In contrast, voglibose did not affect FMD. To confirm this result and determine whether it is a class effect, we conducted another trial (study 2) to compare sitagliptin and alogliptin in 42 T2DM patients (66±8 years) for 6 weeks with 4-week washout periods. Both DPP-4Is improved glycemic control but significantly attenuated FMD (7.2/4.3%, P<0.001, before/after sitagliptin; 7.0/4.8%, P<0.001, before/after alogliptin, respectively). Interestingly, FMD reduction was less evident in subjects who were on statins or whose LDL cholesterol levels were reduced by them, but this was not correlated with parameters including DPP-4 activity and GLP-1 levels or diabetic parameters. CONCLUSIONS Our 2 independent trials demonstrated that DPP-4 inhibition attenuated endothelial function as evaluated by FMD in T2DM patients. This unexpected unfavorable effect may be a class effect of DPP-4Is. CLINICAL TRIAL REGISTRATION URL: http://center.umin.ac.jp, Unique Identifiers: UMIN000005682 (sitagliptin versus voglibose) and UMIN000005681 (sitagliptin versus alogliptin).
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9.
Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents.
Philis-Tsimikas, A, Del Prato, S, Satman, I, Bhargava, A, Dharmalingam, M, Skjøth, TV, Rasmussen, S, Garber, AJ
Diabetes, obesity & metabolism. 2013;(8):760-6
Abstract
AIM: The efficacy and safety of insulin degludec (IDeg), a new basal insulin with an ultra-long duration of action, was compared to sitagliptin (Sita) in a 26-week, open-label trial. METHODS Insulin-naïve subjects with type 2 diabetes [n = 458, age: 56 years, diabetes duration: 7.7 years, glycosylated haemoglobin (HbA1c): 8.9% (74 mmol/mol)] were randomized (1 : 1) to once-daily IDeg or Sita (100 mg orally) as add-on to stable treatment with 1 or 2 oral antidiabetic drugs (OADs). RESULTS Superiority of IDeg to Sita in improving HbA1c and fasting plasma glucose (FPG) was confirmed [estimated treatment difference (ETD) IDeg-Sita for HbA1c: -0.43%-points [95% confidence interval (CI): -0.61; -0.24, p < 0.0001] and for FPG: -2.17 mmol/l (95% CI: -2.59; -1.74, p < 0.0001)]. HbA1c < 7% (<53 mmol/mol) was achieved by 41% (IDeg) versus 28% (Sita) of patients, estimated odds ratio IDeg/Sita: 1.60 (95% CI: 1.04; 2.47, p = 0.034). There was no statistically significant difference in the rate of nocturnal confirmed hypoglycaemia between IDeg and Sita [0.52 vs. 0.30 episodes/patient-year, estimated rate ratio (ERR): IDeg/Sita: 1.93 (95% CI: 0.90; 4.10, p = 0.09)]. Rates of overall confirmed hypoglycaemia were higher with IDeg than with Sita [3.1 vs. 1.3 episodes/patient-year, ERR IDeg/Sita: 3.81 (95% CI: 2.40; 6.05, p < 0.0001)]. IDeg was associated with a greater change in body weight than Sita [ETD IDeg-Sita: 2.75 kg (95% CI: 1.97; 3.54, p < 0.0001)]. The overall rates of adverse events were low and similar for both groups. CONCLUSIONS In patients unable to achieve good glycaemic control on OAD(s), treatment intensification with IDeg offers an effective, well-tolerated alternative to the addition of a second or third OAD.
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A randomized, double-blind, comparative therapy evaluating sitagliptin versus glibenclamide in type 2 diabetes patients already treated with pioglitazone and metformin: a 3-year study.
Derosa, G, Cicero, AF, Franzetti, IG, Querci, F, Carbone, A, Piccinni, MN, D'Angelo, A, Fogari, E, Maffioli, P
Diabetes technology & therapeutics. 2013;(3):214-22
Abstract
OBJECTIVES This study evaluated if triple oral therapy can be useful in improving glycemic control compared with metformin monotherapy and with a metformin and pioglitazone combination. Furthermore, we also compared a triple metformin+pioglitazone+glibenclamide combination with a metformin+pioglitazone+sitagliptin one. SUBJECTS AND METHODS After a 2-year run-in therapy-augmenting phase with metformin and pioglitazone, 453 overweight, type 2 diabetes patients were randomized to 1 year of sitagliptin versus 1 year of glibenclamide to evaluate, as the primary outcome, the variation of β-cell function both in a fasting state and after an euglycemic hyperinsulinemic and hyperglycemic clamp. As secondary outcomes we evaluated glycemic control and insulin resistance. RESULTS Both the triple therapy combinations were more effective in reducing glycated hemoglobin compared with metformin monotherapy and with dual therapy metformin+pioglitazone. Fasting plasma insulin level and the homeostasis model assessment insulin resistance index were significantly increased by triple therapy with glibenclamide and decreased by the one with sitagliptin. Although sitagliptin did not change the homeostasis model assessment β-function index, this value was significantly increased by glibenclamide. The fasting plasma proinsulin level was decreased by sitagliptin. Triple therapy with sitagliptin greatly improved β-cell function measures compared with the glibenclamide one and also compared with metformin monotherapy and with the metformin+pioglitazone combination. CONCLUSIONS Dual combination therapy is more effective than monotherapy in improving glycemic control. When double therapy is not enough to reach an adequate glycemic control, sitagliptin should be preferred to glibenclamide as the third agent because of its positive effect on β-cells.